The overall aim of Project 2 is to establish the physical basis for weakened cell-cell adhesion and enhanced motility in cancer metastasis and how mechanical tension regulates these functions. Tumor cells adhere to one another less well than their corresponding normal cell counterparts. The discovery of cell surface cadherin adhesive receptors and associated cytosolic catenins as key regulators of tissue architecture during development and adult tissue homeostasis provides molecular candidates that could explain altered cell adhesion in cancer. The disruption of the cadherin-catenin adhesive complex correlates with clinical features of tumor metastasis and poor patient prognosis. Thus, the cadherin-catenin adhesive complex is an important determinant of tumor progression by functioning to suppress tumor invasion and metastasis. Following disruption of the cadherin-catenin adhesive complex, tumor cells de-adhere from one another, invade the surrounding ECM, and migrate away from the primary tumor. How tumor cells invade the ECM may provide critical therapeutic targets for the prevention of cancer metastasis. In four inter-related aims we will test the hypotheses that cadherin-mediated adhesion forces on adjoining cells are regulated by cancer mutations in cytoplasmic proteins recruited to the cadherin adhesive receptor complex, which affect tumor intercellular adhesion, tumor invasion and metastasis and that once tumor cells de-adhere from one another, focal adhesion proteins regulate tumor cell invasion in the surrounding 3D matrix, the propulsive forces of migration, and mechanical tension sensing of the matrix. Linkage to PS-OC: The research aims of Project 2 fit the overarching theme of the Center of the role of forces in the metastatic cascade; Aims 1-4 are synergistically connected to Aims 1 and 2 in Project 1 and Aim 4 in Project 3 for further research integration of the Center; all Students and Fellows in the Project will be enrolled in the Center Training Program; this project will make use of the resources provided by the Imaging Core and Microfabrication Core, as well as the Administrative Unit of the Center; cell lines and micromechanical methods will be the same as those used in all projects; computational efforts will be shared among all projects.